AIM2靶向FN1抑制肝癌细胞转移的机制研究

Tumor invasion and metastasis are responsible for the poor prognosis of hepatocellular carcinoma (HCC). However, the underlying mechanism remains elusive. Our preliminary data showed that the expression of AIM2 in HCC was decreased and significantly correlated with vascular invasion, lymph node metastasis and poor prognosis. Downregulation of AIM2 markedly induced the expression of FN1, and promoted cell migration and invasion. Furthermore, AIM2 expression was modulated by HBx. Collectively, we assume that AIM2 inhibits cell migration and invasion of HCC by targeting FN1. In this study, we aim to determine the expression of AIM2 and FN1 and the relevant clinical significance in HCC, to disclose the effect of HBx on AIM2, to unveil the mechanism of AIM2-mediated regulation of FN1 expression, and to reveal the role of HBx/AIM2/FN1 signaling pathway in cell migration and invasion in HCC, using a series of biological and immunological experiments in cell and animal models. Our study is likely to provide not only solid evidence that AIM2 is involved in HCC progression, but also a promising therapeutic target in HCC.

浸润转移是导致肝细胞癌预后差的主要因素，但其分子机制尚未明了。我们前期观察到AIM2在肝癌细胞及组织中低表达，并与血管侵犯、淋巴结转移及预后差相关；基因芯片及细胞实验结果表明沉默AIM2显著上调FN1表达，并促进肝癌细胞迁移；此外，AIM2表达受HBx调控。因此，我们提出AIM2靶向FN1，抑制肝癌细胞转移的假说。本项目拟采用一系列分子细胞生物学和免疫学实验，利用多种细胞株和动物模型，在细胞功能及蛋白表达调控上，明确AIM2和FN1在肝癌中的表达及临床意义，揭示HBx调控AIM2的作用机制，探讨AIM2对FN1的调控作用，阐述HBx/AIM2/FN1通路在肝癌细胞转移中的作用及其分子机制，从而获得AIM2参与肝癌恶性进程的可靠证据，为寻找肝癌治疗新靶点和诠释肝癌发生发展的分子机制提供科学依据。

肿瘤转移是导致肝细胞癌（HCC）患者高死亡率的原因。AIM2（absent in melanoma2）参与炎症和致癌过程，但是其在HCC转移中的作用机制尚不清楚。在本项目研究中，我们发现了AIM2蛋白在HCC细胞株和临床样品中的表达明显降低。AIM2低表达与HCC患者血清AFP水平升高、脉管浸润、分化差、肿瘤包膜不完整以及术后生存率不佳密切相关。体外研究结果表明，乙型肝炎病毒X蛋白（HBx）在转录和翻译后水平上调控AIM2的表达。过表达HBx通过增强EZH2蛋白的稳定性显着阻断AIM2 mRNA和蛋白水平的表达。此外，HBx与AIM2协同泛素化诱导增强了AIM2降解程度。细胞功能上，敲低AIM2促进HCC细胞迁移、伪足形成、划痕实验及肿瘤转移能力，过表达AIM2则抑制以上功能。AIM2靶向抑制纤连蛋白1（FN1）的表达并诱导上皮-间充质转化（EMT）通路的激活。沉默FN1可显著阻止下调AIM2诱导的HCC细胞迁移。这些数据表明HBx下调AIM2的表达并诱导EMT过程促进HCC转移，与HCC患者预后不良密切相关。因此，本研究的结果表明AIM2是乙肝病毒相关HCC的潜在预后生物标志和肿瘤转移的治疗靶标。